The implantable cardioverter defibrillator (ICD) is the most effective means of detecting and treating arrhythmias, such as ventricular tachycardia (VT) or ventricular fibrillation (VF). However, despite its rapid acceptance, the main limitation of the current ICD technology is that it aims to terminate an arrhythmia only after the arrhythmia has started. Given that failure, delay or false detection in detecting VT/VF is a life- threatening concern, it is imperative that the next generation of ICD technology is able to prevent arrhythmias from starting rather than terminating them after their initiation. Electrical alternans is a pattern of variation in the shape of electrocardiographic waveform that appears on an every other beat basis. Alternation in ventricular repolarization, namely repolarization alternans (RA), has been associated with increased vulnerability to VT/VF and sudden cardiac death (SCD) in patients with heart failure. Thus, in this R21 grant application, we propose to investigate the hypothesis that therapy application by an ICD before the abnormal heart rhythm develops will provide a significant improvement not only in preventing SCD but also in patient acceptance of ICD therapy and quality of life. We have developed a system that can both estimate RA in real- time from intracardiac electrograms and deliver electrical pulses that are timely coupled to the cardiac electrical activity. In this proposal we will investigate the applicability of RA-triggered delivery of clinically appropriate electrical therapy to suppress/terminate RA and prevent the development of VT/VF in an animal model of chronic myocardial infarction. To achieve the aims of this proposal we will (i) establish criteria for the detection of statistically significant RA preceding the onset of a tachyarrhythmic event in a swine animal model, (ii) develop effective algorithms to trigger electrical therapy and investigate the efficacy of electrical therapy in reducing/suppressing the level of RA preceding the onset of a tachyarrhythmic event. PUBLIC HEALTH RELEVANCE: The implantable cardioverter defibrillator (ICD) is a device that detects arrhythmias, such as VT or VF, and terminates them by delivery of one or more electrical impulses to the heart. However, failure, delay or false detection in detecting VT or VF are of great concern. This research proposal investigates the application of therapy by an ICD before the abnormal heart rhythm develops, thus providing a significant improvement not only in preventing sudden cardiac death but also in patient acceptance of ICD therapy and quality of life.